Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. E. et al as reported in Khim-Farmastsevt. Zh. 10, No. 11, 56-60 (1976); C.A. 86: 155489r exemplified by the compound: 5-aminosulfonyl-N-(1-azabicyclo-[2.2.2]oct-3-yl)-2-methoxybenzamide. This compound and others in the series were reported by the authors not to have anti-emetic activity. The above named compound was reported in USSR Pat. No. SU-414-261 to have neuroleptic activity. The compounds of the present invention show anti-emetic activity without the neuroleptic activity associated with dopamine D.sub.2 -receptor blockade (blockade of d-amphetamine lethality in mice).
Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide and N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al in Khim-Farmatsevt. Zh. 7, 20-24 (1974); C.A. 79: 146358a and the latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65: 2220b. The compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention.
Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid e was reported in Ger. Offen. No. 2,548,968; C.A. 87: 68001c and equivalently related U.S. Pat. No. 4,093,734 from 4-amino-3-chloro-5-trifluoromethylbenzoic acid chloride and 3-aminoquinculidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics.
G.B. 2,160,871A describes ether and thioether benzamide derivatives of dialkylaminoalkylamine or 1-alkyl-4-aminopiperidines that are useful in the treatment of emesis, and also the treatment of impaired gastric motility disorders. The patent compounds are analogs of metoclopramide and clebropride.
U.S. Pat. Nos. 4,593,034; 4,657,911; and 4,717,563 describe benzoyl derivatives of 1-azabicyclo[2.2.2]octan-3-amine (3-aminoquinuclidine) and 1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) which exhibit gastric prokinetic and antiemetic effects in warm blooded animals.
U.S. Pat. No. 4,722,834 describes 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide-N-oxides which are useful for the control of emesis caused by administration of anticancer drugs to warm blooded animals.
There is continuing interest in the development of quinuclidine derivatives which exhibit a novel combination of therapeutic properties for the treatment of disorders in warm blooded animals, with minimal neuropharmacological side effects.
Accordingly, it is an object of this invention to provide a novel class of N-[(2-dialkylaminomethyl)-3-quinuclidinyl]benzamides and thiobenzamides, and corresponding carboxylates.
It is another object of this invention to provide quinuclidine derivatives which exhibit gastric prokinetic, antiemetic, anxiolytic and selective 5-HT(serotonin) antagonist effects in warm blooded animals.
It is a further object of this invention to provide a method for the treatment of impaired gastrointestinal motility and/or emesis and/or anxiety in warm blooded animals.
Other objects and advantages of the present invention shall become apparent from the accompanying description and examples.